Toxic Keratopathy Following the Use of Alcohol-Containing Antiseptics in Nonocular Surgery

Importance  Corneal abrasion is the most common ocular complication associated with nonocular surgery, but toxic keratopathy is rare.

Observation  Three patients developed severe toxic keratopathy after orofacial surgery on the left side with general anesthesia. All patients underwent surgery in the right lateral tilt position with ocular protection but reported irritation and redness in their right eyes after the operation. Alcohol-containing antiseptic solutions were used for presurgical preparation. Ophthalmic examination showed decreased visual acuity ranging from 20/100 to 20/400, corneal edema and opacity, anterior chamber reaction, or stromal neovascularization in the patients’ right eyes. Confocal microscopy showed moderate to severe loss of corneal endothelial cells in all patients. Despite prompt treatment with topical corticosteroids, these 3 patients eventually required cataract surgery, endothelial keratoplasty, or penetrating keratoplasty, respectively. After the operation, the patients’ visual acuity improved to 20/30 or 20/40. Data analysis was conducted from December 6, 2010, to June 15, 2015.

Conclusions and Relevance  Alcohol-containing antiseptic solutions may cause severe toxic keratopathy; this possibility should be considered in orofacial surgery management. Using alcohol-free antiseptic solutions in the periocular region and taking measures to protect the dependent eye in the lateral tilt position may reduce the risk of severe corneal injury.

Although they are rare, eye injuries ranging from corneal abrasion to serious corneal edema occur during nonocular surgery.^1,2 Various ocular protective strategies during general anesthesia have been proposed, but corneal injury still occurs because of incorrect placement of tape or unwise use of surgical preparation solutions.^3-5 Here, we report 3 cases of severe toxic keratopathy in the right eye after orofacial surgery performed on the left side. Alcohol-containing antiseptic preparation solution was used for skin preparation with eye protection. We examined possible pathogenic mechanisms and describe the management of this ocular complication. Data analysis was conducted from December 6, 2010, to June 15, 2015. The National Taiwan University Hospital Institutional Review Board approved this study. All patients provided verbal consent.

Box Section Ref ID

A man in his 60s experienced pain and decreased vision in the right eye after excision of a tumor on the left tongue. On initial examination, best-corrected visual acuity (BCVA) was 20/50 OD and 20/25 OS. Biomicroscopy showed an epithelial defect and corneal edema in the right lower cornea with a trace anterior chamber reaction, while the left eye was unremarkable. Treatment with fluorometholone and tetracycline, 0.1%, ointment was started. Thereafter, corneal edema increased and keratic precipitates were observed. The patient was referred to a corneal specialist (Y.-C.H.) and was treated with prednisolone acetate, 1%, for 1 month. Betamethasone sodium phosphate, 0.1%, or fluorometholone, 0.1%, was used for a further 3 months. Six months later, a faint opacity persisted in the lower paracentral region of the right cornea. The patient developed a cataract, and BCVA decreased to 20/100 OD. Because the remaining corneal opacity was faint and superficial and corneal endothelial cell density was approximately 1228 cells/mm², cataract surgery was performed in the right eye. The patient’s BCVA improved to 20/30 OD, with a refraction of +0.25 −2.25 × 120° after surgery (Figure 1A and B).

A man in his mid-40s developed redness and pain in his right eye after surgery for left lower gingival cancer. Biomicroscopy revealed ciliary injection, diffuse superficial punctuate keratopathy, Descemet membrane folds, and anterior chamber reaction in the right eye. Topical betamethasone, 0.1%, was applied, and the symptoms gradually resolved within 1 week. However, corneal microcystic edema persisted and was accompanied by superficial corneal opacities and intrastromal neovascularization in the upper nasal area (Figure 1C). The patient’s BCVA decreased to 20/100 OD. Descemet stripping automated endothelial keratoplasty was performed 6 months later. Three years after endothelial keratoplasty, the corneal graft remained clear, and visual acuity was 20/30 OD with a refraction of +0.5 + 2.0 × 165° (Figure 1D).

A man in his mid-60s presented with an irritated right eye following surgery for left nasal tumor. Severe corneal edema was noted, and visual acuity was 20/400 OD. Topical betamethasone, 0.1%, hypromellose, 0.32%, and sodium chloride, 5%, hypertonic solution were administered. Although the corneal edema slowly decreased, band keratopathy developed centrally along with peripheral corneal neovascularization in the lower nasal area 7 months later (Figure 1E). Lamellar keratectomy was performed to remove superficial corneal opacities on the right eye. Thereafter, poor corneal reepithelialization was noted because of limbal insufficiency. Despite complete reepithelialization after topical 20% autologous serum use every 2 hours for 2 months, vision improved only slightly because of residual corneal opacity, edema, and cataract. Therefore, penetrating keratoplasty and cataract surgery were performed on the right eye 2 years after the initial presentation. Thereafter, BCVA improved to 20/40 OD with a refraction of −0.25 −4.5 × 125°. The patient later developed peripheral iridocorneal synechia in the lower nasal region (Figure 1F). The graft remained clear 2 years after transplant.

In all patients, orofacial surgery on the left side with eye protection was performed under general anesthesia in the right lateral tilt position. The antiseptic agents used in the surgical fields in all patients contained alcohol: povidone-iodine, 10%, in 70% alcohol in patients 1 and 3 and chlorhexidine, 2%, in 70% isopropyl alcohol in patient 2. Confocal microscopy showed marked polymegathism and pleomorphism with prominent nuclei, indicating cellular stress, in right endothelial cells but not in the left eye in all patients (Figure 2). The initial endothelial cell density of the right eye vs the left eye was 966 vs 3477, 1263 vs 2469, and 1909 vs 3146 cells/mm² in patients 1, 2, and 3, respectively. Corneal endothelial cell density in patient 3 rapidly decreased to 560 cells/mm² three months after the initial presentation. The histopathologic findings of the corneal button from patient 3 showed hypocellular stroma, focal edematous collagens with loosening arrangement, intrastromal neovascularization, and markedly sparse endothelial cells.

Corneal injury is the most common perioperative eye injury in nonocular surgery, especially orofacial surgery.³ Our 3 patients who underwent orofacial surgery in the right lateral tilt position developed severe corneal injuries in the dependent eyes. Alcohol-containing antiseptic agents were used in all patients along with ocular protection during the procedure. Povidone-iodine is considered safe for ophthalmic use, such as conjunctival sac irrigation or instillation.⁶ Despite the possibility of iodine-related allergy, limited cases of povidone-iodine–related allergy in nonocular fields have been reported.⁷ Another possibility may be exposure keratopathy. However, a study showed that exposure keratopathy with general anesthesia manifests mainly as corneal abrasion.⁸ In contrast, our patients developed stromal whitening and an anterior chamber reaction. Exposure keratopathy is less likely to cause such presentations as those witnessed in our patients. Thus, we reasonably postulated that these toxic keratopathies could be related to the alcohol in the antiseptic agents, although we found no reported cases in the literature.

A previous study showed that only povidone-iodine, 10%, solutions without detergent were less toxic to the cornea than other preparations.⁹ Corneal exposure to chlorhexidine and other detergents may cause epithelial defects and corneal edema with endothelial disruption.^10,11 We speculated that alcohol caused the toxic keratopathy in our 3 patients, but chlorhexidine might have also played a role in patient 2. Alcohol can markedly decrease corneal epithelial cell viability and increase proinflammatory cytokine and chemokine expression in both corneal epithelial and stromal cells.¹² Even brief alcohol exposure of the corneal surface can disrupt corneal epithelium integrity and induce inflammation.¹³ Nevertheless, alcohol-assisted epithelial removal is widely used in refractive surgery. The commonly used concentration ranges from 10% to 20% with a duration of less than 1 minute, which is a much shorter exposure period and more diluted concentration than in our patients. An animal study showed that alcohol could cause marked corneal edema and anterior chamber inflammation within 24 hours.¹⁴ Later sequelae included corneal opacity, stromal neovascularization, reduced endothelial cell density, and adherence of the iris to the retrocorneal membrane. Our findings are consistent with those in these reports and strongly suggest that alcohol is toxic to the cornea.

The lateral or prone position is associated with an increased risk of ocular injury.¹⁵ The lateral tilt position may increase the chance of chemicals accumulating in the eyelid medial commissure, resulting in a greater risk of damage to the nasal and inferior cornea of the dependent eye. Furthermore, anesthesia inhibits the protective Bell phenomenon and reduces tear production, and longer surgical procedures cause greater ocular vulnerability. Therefore, particular care should be taken when using antiseptic preparations on the face and in the periocular regions, even while using eye protection. Extra attention should be paid to the eyelid medial commissure of the dependent eye when patients undergo orofacial surgery in the lateral tilt position.

Alcohol-containing antiseptic agents used during orofacial surgery may cause toxic keratopathy, and cataract surgery, endothelial keratoplasty, or penetrating keratoplasty may be required to restore vision. Using alcohol-free antiseptic agents may reduce the risk of corneal injury in orofacial surgery.

Submitted for Publication: September 20, 2015; final revision received January 4, 2016; accepted January 5, 2016.

Corresponding Author: Yu-Chih Hou, MD, Department of Ophthalmology, National Taiwan University Hospital, College of Medicine, National Taiwan University, 7 Chung-Shan South Rd, Taipei, Taiwan (ychou51@ntu.edu.tw).

Published Online: February 25, 2016. doi:10.1001/jamaophthalmol.2016.0001.

Author Contributions: Dr Hou had full access to all the study data and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kuo, Hou.

Acquisition, analysis, or interpretation of data: Liu, Yeh, Huang, Lin, Hou.

Drafting of the manuscript: Liu, Yeh, Kuo, Hou.

Critical revision of the manuscript for important intellectual content: Liu, Huang, Lin, Hou.

Administrative, technical, or material support: Yeh, Kuo, Huang, Hou.

Study supervision: Hou.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.